The treatment landscape for mCRPC is continually advancing. At this stage, therapeutic options encompass taxane-based chemotherapies, androgen receptor pathway inhibitors (ARPI), poly ADP ribose polymerase inhibitors (PARPi), Radium-223 and radioisotope therapies targeting Prostate Specific Membrane Antigen (PSMA). Nevertheless, achieving sustained remission remains a formidable challenge due to tumor heterogeneity and the development of acquired resistance.3,4 Given that mCRPC remains a lethal condition, there is a continuous need and interest in developing new treatments. One of the most promising approaches is theranostics, which involves targeting cancer cells with PSMA-targeted radioligands. Since PSMA is highly expressed in cancer cells, combining PSMA-617 with beta-emitting lutetium enables the targeted delivery of beta-particle radiation to PSMA-expressing cells.5,6
The VISION trial showed that treatment with Lutetium-177 (177Lu)-PSMA-617 improved radiological progression-free survival and extended overall survival (OS) compared to standard treatments in patients whose disease had progressed following prior ARPI and one or two lines of taxane-based chemotherapy.7 The TheraP trial demonstrated that in patients with mCRPC who had progressed after docetaxel treatment, (177Lu)-PSMA-617 offered OS comparable to cabazitaxel, but with a more favorable side effect profile, higher response rates, and enhanced patient-reported outcomes.8
Identifying prognostic markers is essential for determining the optimal treatment sequence in the castration-resistant phase and recognizing patients who will benefit from treatment. These markers are vital for predicting patient survival and guiding informed treatment decisions within a complex therapeutic landscape.9
Systemic inflammation is recognized as a significant risk factor for cancer development and progression. Markers derived from peripheral blood count indices have garnered considerable attention as indirect indicators of the inflammatory response in cancer.10 The pan-immune inflammation value (PIV) is a systemic inflammation indicator derived from the complete blood count, encompassing all cellular components. This readily accessible biomarker has the potential to reflect both the body's immune response and the state of systemic inflammation.11
In our study, we aimed to assess the prognostic significance of PIV in patients with mCRPC undergoing treatment with (177Lu)-PSMA-617 radioligand therapy.
PIV was calculated using the formula outlined in previous studies:12 [(neutrophils (10³/mm³) × monocytes (10³/mm³) × platelets (10³/mm³))] / [(lymphocytes (10³/mm³)]. All laboratory values for PIV were obtained from results within the week preceding the initiation of (177Lu)-PSMA-617 radioligand therapy. A definitive cut-off point for PIV has not been established. Given the common use of the median value as a cut-off in the literature, we adopted this approach, dividing the patients in our study into two groups: PIV-low and PIV-high, based on the median PIV value.13-16 We excluded patients with active infectious diseases that could influence the PIV index, those with a history of intravenous or oral antibiotic use before treatment, individuals using corticosteroids for any reason, and those with a second primary malignancy (The study protocol is shown in figure 1).

Figure 1. Study Design
Upon evaluating data from 320 patients diagnosed with mCRPC, we analyzed 43 patients who received (177Lu)-PSMA-617 treatment. Baseline demographic and clinicopathological characteristics were similar between the two groups. However, the incidence of lung metastases detected before (177Lu)-PSMA-617 treatment was higher in the high PIV group (33.3% vs. 13.6%, p=0.162). Additionally, 90.9% of patients in the low PIV group and 85.7% in the high PIV group had undergone at least two lines of therapy before (177Lu)-PSMA-617 (p=0.477). In terms of sequential therapies, both low PIV (59.0%) and high PIV (66.6%) groups received cytotoxic chemotherapy and ARPI treatments (p=0.595). The demographic, clinical, and pathological characteristics of the patients according to PIV groups are shown in Table 1.

The median OS was calculated to be 7.8 months (95% CI 3.5-12.1) for all patients, while it was 6.0 months (95% CI: 2.7-9.3) in patients with lung metastases and 11.8 months (95 %CI: 4.2-19.4) in patients without lung metastases (p=0.037). The median OS was also longer in patients with ECOG PS of 0 or 1 (23.4 months (95% CI 19.2-27.7)) than those with ECOG PS of ≥ 2 (8.1 months (95% CI 1.3-15.0)) (p<0.001). In the analysis based on patients' pretreatment lactate dehydrogenase (LDH) levels, the median OS was 9.5 months (95% CI 4.8-14.2) in the group with LDH < 1.5 times the upper limit of normal (ULN), while it was 1.7 months (95% CI 0-5.3) in the group with LDH ≥ 1.5 times the ULN (p=0.010) (Table 2).

When evaluating OS between PIV groups, the median OS in the low PIV group [15.1 months (95% CI 10.6-19.5)] was longer compared to the high PIV group [4.2 months (95% CI 1.7-6.6)], and the difference between the survival outcomes was statistically significant (p<0.001 Figure 2).

Figure 2: Kaplan-Meier Projection of Overall Survival in PIV Groups
In multivariable analysis, high PIV (HR: 4.3, 95% CI 1.194-15.93, p=0.026) and high ECOG PS (HR: 7.05, 95% CI 1.48-33.46, p=0.014) were associated with shorter OS (Table 3).

We observed that a higher pretreatment PIV was associated with shorter OS in patients treated with (177Lu)-PSMA-617.17 Additionally, our previous study demonstrated the prognostic role of PIV in mCRPC patients treated with ARPI.18 These findings suggest a potential link between PIV and prognosis in mCRPC patients. In the post-hoc VISION trial analysis, PIV was identified as a predictive marker for OS; however, its prognostic impact was not demonstrated.19 In the VISION trial, standard care therapies—including hormonal treatments like abiraterone and enzalutamide, radiation therapy, or any dosage of glucocorticoids—were permitted alongside the (177Lu)-PSMA-617 therapy.7 In our study, patients were exclusively treated with (177Lu)-PSMA-617. These standard treatments might have influenced the PIV index by altering the cellular parameters of the complete blood count, potentially obscuring the prognostic impact of PIV.
Approximately 22%–30% of patients with mCRPC will present with visceral metastases. The presence of visceral metastases, particularly those affecting the liver, is associated with a poor prognosis, as they are regarded as a marker of more aggressive disease.20-22 Our study did not identify an association between the presence of liver metastases before (177Lu)-PSMA-617 treatment and survival. However, the data indicated that lung metastases were associated with shorter OS. The limited number of patients with liver metastases before (177Lu)-PSMA-617 treatment may have prevented us from demonstrating a difference in survival outcomes between patients with and without liver metastases.
The clinical implications of this study are constrained by its small sample size, lack of randomization, and single-center design. While PIV shows potential as a prognostic marker for patients with mCRPC undergoing (177Lu)-PSMA-617 treatment, the current data are insufficient to support its routine use in clinical practice. Larger, multicenter studies with prospective validation are necessary to determine whether PIV can reliably predict outcomes and guide treatment decisions in this population. Until these findings are validated in larger studies, the clinical utility of PIV should be considered preliminary and not yet ready for integration into practice.
In conclusion; PIV is emerging as a promising prognostic marker for patients with mCRPC receiving (177Lu)-PSMA-617. Early identification of patients who do not benefit from this treatment could facilitate timely treatment decisions and discontinuation, thereby reducing drug toxicity and treatment costs, and allowing for the earlier initiation of alternative treatment regimens.
Written by: Satı Coşkun Yazgan,1,2 Emre Yekedüz,3 Mine Araz,4 Hatice Bölek,1,2 N.Özlem Küçük,4 Yüksel Ürün1,2
- Department of Medical Oncology, Ankara University Faculty of Medicine, Ankara, TÜRKİYE
- Cancer Research Institute, Ankara University, Ankara, TÜRKİYE
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Nuclear Medicine, Ankara University Faculty of Medicine, Ankara, TÜRKİYE
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